Electrical stimulation of the mesencephalic locomotor region (MLR) is known to initiate and maintain walking in the brainstem- transected animal by modulating locomotion oscillators present in the spinal cord. Over the past several years we have described much of the anatomical and functional organization of the MLR. Recently, we developed a technique for chemically controlling locomotion using localized injections of putative neurotransmitters into various linked brainstem areas. These studies revealed that certain aspects of locomotion (frequency, duration, onset) may be under differential neurochemical control. That is, each aspect may be modulated by the use of a different neurotransmitter. The proposed research will use two approaches, one adult and one developmental. These studies will provide information on the three main elements needed for walking - postural stability, progressive movement and rhythm generation. One series will investigate the differential neurochemical control of each aspect of locomotion in the MLR, the medioventral medulla (the area receiving MLR output) and the spinal cord (the area receiving medulla output). Localized injections of putative neurotransmitters into each of these regions will be made to identify and characterize the neuroactive substances involved in controlling progression (frequency, duration, onset). Another series will employ electrical stimulation of two regions known to activate or inhibit postural tone exclusive of locomotion. Combination of this technique with chemical induction of walking should provide a preparation with consistent postural stability and progression. The developmental series will be used to determine the ontogeny of rhythms related to walking. The in vitro brainstem-spinal cord preparation will be used to screen neurotransmitters for the other series and to help describe (along with in vivo studies) the developmental influences which mark the sequence of changes from spinal to supraspinal control, from digitigrade to plantigrade mode, of locomotion. These studies are aimed at developing model systems for the study of normal and abnormal movement, and at the design of neurochemical strategies for the treatment of disorders involving locomotor dysfunction. In addition, a major thrust of the research is directed at the development of appropriate electrochemical prostheses to induce and maintain locomotion in the diseased or denervated state.